Calcium-sensing receptor-active compounds

Abstract

Compounds of general formula (I) their use as calcium receptor-active compounds for the prophylaxis, treatment or amelioration of physiological disorders or diseases associated with disturbances of CaSR activity, such as hyperparathyroidism, pharmaceutical compositions comprising said compounds, and methods of treating diseases with said compounds.

1 . A compound according to formula I 
       
         
           
           
               
               
           
         
         wherein 
         R 1  represents hydrogen, halogen, hydroxy, C 1-4 alkyl, trifluoromethyl or C 1-4 alkoxy; 
         R 2  represents hydrogen, halogen, hydroxy, C 1-4 alkyl, trifluoromethyl or C 1-4 alkoxy; 
         R 3  represents C 1-6 alkyl; 
         R 4  represents —C(O)NH 2 , C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, haloC 1-6 alkyl, aminoC 1-6 alkyl, hydroxyC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 2-5 heterocycloalkyl comprising 1-4 hetero atoms selected from N, O and S, C 2-5 heterocycloalkenyl comprising 1-4 hetero atoms selected from N, O and S, aminosulfonylC 1-6 alkyl, C 1-3 alkylsulfonylC 1-6 alkyl, C 1-3 alkylsulfonylaminoC 1-3 alkyl, C 6-12 aryl, C 1-11 heteroaryl comprising 1-4 hetero atoms selected from N, O and S, 
         wherein said C 2-6 alkenyl, C 2-6 alkynyl, C 1-6 alkoxy, C 1-6 alkylamino, aminoC 1-6 alkyl, hydroxyC 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkenyl, C 2-5 heterocycloalkyl comprising 1-4 hetero atoms selected from N, O and S, C 2-5 heterocycloalkenyl comprising 1-4 hetero atoms selected from N, O and S, aminosulfonylC 1-6 alkyl, C 1-3 alkylsulfonylC 1-6 alkyl, C 1-3 alkylsulfonylaminoC 1-3 alkyl, C 6-12 aryl or C 1-11 heteroaryl comprising 1-4 hetero atoms selected from N, O and S, is optionally substituted with one or more, same or different substituents selected from the group consisting of halogen, trifluoromethyl, hydroxy, mercapto, cyano, carboxy, —C(O)H, —NH 2 , —C(O)NH 2 , nitro, —S(O) 2 NH 2 , C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, hydroxyC 1-6 alkyl, haloC 1-6 alkyl, C 1-4 alkoxy, C 1-6 alkylamino, or phenyl; 
         or pharmaceutically acceptable stereoisomers or salts thereof. 
       
     
     
         2 . A compound according to  claim 1 , represented by formula Ia or Ib 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound according to  claim 1 , wherein R 3  represents methyl. 
     
     
         4 . A compound according to  claim 1 , wherein R 1  represents chloro, fluoro, methoxy or ethoxy. 
     
     
         5 . A compound according to  claim 1 , wherein R 2  represents chloro, fluoro, methoxy or ethoxy. 
     
     
         6 . A compound according to  claim 1 , wherein R 1  represents 4-fluoro and R 2  represents 3-methoxy. 
     
     
         7 . A compound according to  claim 1 , wherein R 1  represents chloro and R 2  represents hydrogen. 
     
     
         8 . A compound according to  claim 1 , wherein R 4  represents —C(O)NH 2 , C 1-4 alkoxy, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, aminoC 1-4 alkyl, C 3-6 cycloalkyl, C 2-4 heterocycloalkyl comprising 1-3 hetero atoms selected from N and O, C 2-4 heterocycloalkenyl comprising 1-3 hetero atoms selected from N and O, aminosulfonylC 1-4 alkyl, C 1-2 alkylsulfonylC 1-4 alkyl, C 1-2 alkylsulfonylaminoC 1-3 alkyl, C 2-5 heteroaryl comprising 1-3 hetero atoms selected from N and O,
 wherein said C 1-4 alkoxy, haloC 1-4 alkyl, hydroxyC 1-4 alkyl, C 3-6 cycloalkyl, C 2-4 heterocycloalkyl comprising 1-3 hetero atoms selected from N and O, C 2-4 heterocycloalkenyl comprising 1-3 hetero atoms selected from N and O, aminosulfonylC 1-4 alkyl, C 1-2 alkylsulfonylC 1-4 alkyl, C 1-2 alkylsulfonylaminoC 1-3 alkyl, C 2-5 heteroaryl comprising 1-3 hetero atoms selected from N and O, 
 is optionally further substituted with one or more, same or different substituents selected from the group consisting of halogen, trifluoromethyl, hydroxy, mercapto, cyano, carboxy, —C(O)H, —NH 2 , —C(O)NH 2 , nitro, —S(O) 2 NH 2 , C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, hydroxyC 1-4 alkyl, haloC 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkylamino, or phenyl. 
 
     
     
         9 . A compound according to  claim 8 , wherein R 4  represents —C(O)NH 2 , hydroxyC 1-3 alkyl, methylsulfonylC 1-2 alkyl, or C 2 heteroaryl comprising 3 hetero atoms selected from N, wherein said hydroxyC 1-3 alkyl is optionally substituted with hydroxy. 
     
     
         10 . A compound according to  claim 9 , wherein R 4  represents —C(O)NH 2 , hydroxymethyl, 1,2-dihydroxyethyl, methylsulfonylmethyl or 1,2,4-triazolyl. 
     
     
         11 . A compound according to  claim 1 , selected from the group consisting of
 N-[2-[[4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-benzoyl]amino]ethyl]-1H-1,2,4-triazole-3-carboxamide (Compound 101),   N-[2-(2,3-dihydroxypropanoylamino)ethyl]-4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]benzamide (Compound 102),   4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-N-[2-[(2-hydroxyacetyl)amino]ethyl]benzamide (Compound 103),   N-[2-[[4-[(1R,3 S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]-cyclopentyl]-benzoyl]amino]ethyl]oxamide (Compound 104), or   4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]cyclopentyl]-N-[2-[(2-methylsulfonylacetyl)amino]ethyl]benzamide (Compound 105).   
     
     
         12 . A compound according to  claim 1  for use as a medicament in therapy. 
     
     
         13 . A compound according to  claim 1  for use in the treatment, amelioration or prophylaxis of physiological disorders or diseases associated with disturbances of CaSR activity. 
     
     
         14 . A pharmaceutical composition comprising a compound according to  claim 1  or a pharmaceutically acceptable salt, solvate, hydrate or in vivo hydrolysable ester thereof together with a pharmaceutically acceptable vehicle or excipient. 
     
     
         15 . A method of preventing, treating or ameliorating parathyroid carcinoma, parathyroid adenoma, primary parathyroid hyperplasia, cardiac, renal or intestinal dysfunctions, diseases of the central nervous system, chronic renal failure, chronic kidney disease, polycystic kidney disorder, podocyte-related diseases, primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, anemia, cardiovascular diseases, renal osteodystrophy, osteitis fibrosa, adynamic bone disease, osteoporosis, steroid induced osteoporosis, senile osteoporosis, post-menopausal osteoporosis, osteomalacia and related bone disorders, bone loss post renal transplantation, cardiovascular diseases, gastrointestinal diseases, endocrine and neurodegenerative diseases, cancer, Alzheimer's disease, IBS, IBD, malassimilation, malnutrition, abnormal intestinal motility such as diarrhea, vascular calcification, abnormal calcium homeostasis, hypercalcemia, or renal bone diseases, the method comprising administering to a patient in need thereof an effective amount of a compound according to  claim 1 , optionally in combination or as supplement with an active vitamin-D sterol or vitamin-D derivative, such as 1-α-hydroxycholecalciferol, ergocalciferol, cholecalciferol, 25-hydroxycholecalciferol, 1-α-25-dihydroxycholecalciferol, or in combination or as supplement with phosphate binders, estrogens, calcitonin or biphosphonates. 
     
     
         16 . A compound selected from the group consisting of
 Methyl 4-[(1R)-3-oxocyclopentyl]benzoate (Intermediate 1),   Methyl 4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]-amino]cyclopentyl]-benzoate (Intermediate 2),   4-[(1R,3S)-3-[[(1R)-1-(4-fluoro-3-methoxy-phenyl)ethyl]amino]-cyclopentyl]benzoic acid (Intermediate 3), or   N-(2-Amino-ethyl)-4-{(1S,3R)-3-[(1R)-1-(4-fluoro-3-methoxy-phenyl)-ethylamino]-cyclopentyl}-benzamide (Intermediate 4).   
     
     
         17 . A compound according to  claim 2 , wherein R 3  represents methyl. 
     
     
         18 . A compound according to  claim 2 , wherein R 1  represents chloro, fluoro, methoxy or ethoxy. 
     
     
         19 . A compound according to  claim 3 , wherein R 1  represents chloro, fluoro, methoxy or ethoxy. 
     
     
         20 . A compound according to  claim 2 , wherein R 2  represents chloro, fluoro, methoxy or ethoxy.